The direct Interaction between [unreadable]-amyloid (A[unreadable]) peptide and apolipoprotein E (apoE) has been identified as an important factor affecting A[unreadable] brain clearance, its transport across the blood-brain-barrier (BBB), and the promotion of A[unreadable] fibrillization and deposition in the CNS. The magnitude of this interaction appears to be isoform specific, providing one explanation for the linkage between the apoE4 allele and an increased risk of sporadic Alzheimer's disease (AD). The main research hypothesis set forth in this K02 application is that a therapeutic agent preventing the apoE/A[unreadable] interaction will effectively ameliorate A[unreadable] related pathology of AD. We previously demonstrated that blocking apoE/A[unreadable] binding with a synthetic peptide-A[unreadable]12-28P that mimics the apoE binding site on Ali and was modified for in vivo application and BBB permeability, reduces the burden of parenchymal and vascular A[unreadable] deposition and prevents memory impairment in AD transgenic (Tg) mice (Sadowski et al. AJP,2004;165:937;Sadowski et al. PNAS,2006;103:18787). In this grant proposal, we are planning to develop and characterize non-toxic peptoid compounds, which will be based on the A[unreadable]12-28 sequence but will have improved therapeutic efficacy, BBB penetration, and biostability. We have preliminary data to demonstrate that some peptoid modifications may render compounds p-sheet breakers in addition to their inhibitory effect on apoE/A[unreadable] interaction. We also have preliminary data to show that administration of A[unreadable]12-28P through reverse in vivo microdialysis results in A[unreadable] changes in the brain interstitial fluid (ISF) akin to that associated with apoE knockout in PDAPP Tg mice. We plan to use in vivo microdialysis to characterize the pharmacodynamic effect of newly developed peptoid apoE/A[unreadable] antagonists on ISF A[unreadable] metabolism. We also shall test their effect on A[unreadable] deposition and behavior in AD Tg APP-Sw mice co-expressing various human apoE isoforms in order to predict the therapeutic response in carriers of the various human apoE isoforms. Complementary experiments designed to determine the effect of blocking the apoE/A[unreadable] interaction on AS BBB efflux, the equilibrium between A[unreadable] oligomers and fibril formation, and intraneuronal accumulation of apoE/A[unreadable] complexes are planned to elucidate the full beneficial spectrum of this novel therapeutic approach. RELEVANCE: